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Organic Chemistry Highlights

Total Synthesis

Monday, December 6, 2021
Douglass F. Taber
University of Delaware

The Yokoshima Synthesis of Haliclonin A

Haliclonin A (3), isolated from the marine sponge Haliclona sp. collected in Korean waters, displayed antimicrobial and anticancer activity. In the course of a synthesis of 3, Satoshi Yokoshima of Nagoya University assembled 2 by the cyclization of 1 followed by acid-mediated opening of the intermediate cyclopropane (Angew. Chem. Int. Ed. 2021, 60, 9666. DOI: 10.1002/anie.202016343).

The preparation of 1 began with the symmetrical benzoic acid 4. Birch reduction followed by in situ alkylation with the bromide 5 delivered the bis enol ether 6. Alkylation of the derived dianion with the bromide 7 led to 8 with high diastereoselectivity. Esterification and reduction of the ester set the stage for ring-closing metathesis. Selective hydrogenation of the least hindered alkene then gave the alcohol 9. Acylation with 10 followed by exposure to 11, following the Fukuyama protocol, then completed the construction of 1.

Intramolecular carbene addition converted 1 into the intermediate cyclopropane, that was saponified to give the carboxylic acid. On exposure to camphorsulfonic acid, the cyclopropyl ring opened via intermediate 12. Subsequent deprotonation led to the vinylogous ester 2.

Reduction followed by exposure to MsCl and triethylamine converted the vinylogous ester into the corresponding enone, and the lactone into the enol ether. Conjugate addition then gave 13, with the last two stereogenic centers set. Amide formation between the derived carboxylic acid 14 and the amine 15 led to 16, that was oxidized to 17, having the requisite E alkene. Allylation followed by ring-closing metathesis (not illustrated) then completed the synthesis of haliclonin A (3).

The diene 1 is prochiral. There is the potential, as pointed out by the authors, that an enantioselective cyclopropanation catalyst could set the absolute configuration of the natural product.

D. F. Taber, Org. Chem. Highlights 2021, December 6.